Acute leukemia is a rapidly progressive malignant disease of the bone marrow and blood that results in the accumulation of immature, functionless cells, called blast cells, in the marrow and blood. The accumulation of blast cells in the marrow blocks normal blood cell development. As a result, red cells, white cells and platelets are not produced in sufficient numbers. When the disease originates in a marrow lymphocyte progenitor cell, it results in acute lymphoblastic leukemia (ALL) and when the disease originates in a myeloid progenitor, it results in acute myelogenous leukemia (AML).
ALL is a rapidly progressive cancer that starts by the malignant transformation of a marrow lymphocyte. ALL is the most common type of childhood leukemia, with 3,000 new cases per year in all age groups. The transformed, now malignant, cell multiplies and accumulates in the marrow as leukemic lymphoblasts. The lymphoblasts block normal blood cell-formation in the marrow, resulting in insufficient production of red cells, white cells and platelets.
High-grade lymphomas, also known as aggressive lymphoma, include several subtypes of lymphoma that progress relatively rapidly if untreated. These subtypes include, e.g., AIDS-associated lymphoma, anaplastic large cell lymphoma, Burkitt's lymphoma, diffuse large cell lymphoma, immunoblastic lymphoma, lymphoblastic lymphoma and small noncleaved cell lymphomas. Compared to diffuse large B-cell lymphomas, high-grade lymphomas behave more aggressively, require more intensive chemotherapy, and occur more often in children. Because rapidly dividing cells are more sensitive to anti-cancer agents and because the young patients usually lack other health problems, some of these lymphomas show a dramatic response to therapy. Acute lymphoblastic leukemia and high-grade lymphoma are the most common leukemias and lymphomas in children. These diseases are, for the most part, polyclonal, suggesting that only a few genetic changes are sufficient to induce malignancy.
MicroRNAs (miRNAs) represent a new class of abundant small RNAs that play important regulatory roles at the post-transcriptional level by binding to targeted mRNAs and either blocking their translation or initiating their degradation, according to the degree of complementarity with the target. Since their discovery in 1993 in Caenorhabditis elegans (Lee, R. et al., Cell 75:843-854 (1993)), there have been numerous reports that implicated these tiny molecules in the posttranscriptional regulation of a large array of proteins with very diverse roles, ranging from cell proliferation and differentiation to lipid metabolism (Nairz, K., et al., Dev. Biol. 291:314-324 (2006); Chen, J. F., et al., Nat. Genet. 38:228-233 (2006); Naguibneva, I., et al., Nat. Cell Biol. 8:278-284 (2006); Esau, C., et al., Cell Metab. 3:87-98 (2006); and Gauthier, B. R., et al., Nat. Med. 12:36-18 (2006)).
miRNA profiling of hematopoietic lineages in humans and mice showed that miRNAs are differentially expressed in the course of hematopoietic development, suggesting a potential role in hematopoietic differentiation (Chen, C. Z., et al., Science 303:83-86 (2004); Chen, C. Z., et al., Semin. Immunol. 17:155-165 (2005); and Ramkissoon, S. H., et al., Leuk. Res. 30:643-647 (2006)). We have shown that miR-15a and miR-16-1 are deleted or down-regulated in 68% of cases of chronic lymphocytic leukemia (CLL) (Calin, G. A., et al., Proc. Natl. Acad. Sci. USA 99:15524-15529 (2002); and Calin, G. A., et al., Proc. Natl. Acad. Sci. USA 101:11755-11760 (2004)), and that miRNAs genes are frequently located at fragile sites and genomic regions involved in cancers (Calin, G. A., et al, Proc. Natl. Acad. Sci. USA 101:2999-3004 (2004)). miR155 and BIC (its host gene) transcripts have been shown to accumulate in human B cell lymphomas, especially diffuse large B cell lymphomas (Eis, P. S., et al, Proc. Natl. Acad. Sci. USA 102:3627-3632 (2005)), Hodgkin lymphomas (Kluvier, J., et al., J. Pathol 207:243-249 (2006)), and certain types of Burkitt lymphomas (latency type III Epstein-Barr virus-positive Burkitt lymphoma) (Kluvier, J., et al, Genes Chromosomes Cancer 45: 147-153 (2006)).
Currently, there is an urgent need to produce animal models that can be used to screen for, and identify, candidate agents that have therapeutic potential for the treatment of lymphoproliferative disorders, such as B cell malignancies (e.g., B cell leukemias, B cell lymphomas).